Using primary culture of cerebellar granule cells, we found that both endothelin (ET) and sarafotoxin (ST) at low concentration range (0.1-300nM) caused a robust and concentration-dependent increase of 3H-inositol phosphates. This phosphoinositude (PI) hydrolysis caused by both peptides was dependent on extracellular calcium but was not significantly affected by either organic or inorganic calcium entry blockers. The net increase of ET-induced PI hydrolysis was not significantly altered by the depletion of extracellular sodium. ET-induced PI breakdown was partially inhibited by a phorbol ester but was unaffected by pertussis toxin. Effects of ET and ST were nonadditive, but appeared to be additive to that induced by carbachol, histamine, NE, serotonin, glutamate and maitotoxin. Pre-exposure of cells to ET or ST for 30 seconds to 6 hours resulted in densensitization to subsequent stimulation with each peptide, without affecting subsequent responsiveness induced by carbachol, histamine, NE, serotonin, glutamate and maitotoxin. Thus, cerebellar granule cells appear to express a common population of receptors for ET and ST, which are coupled to PI hydrolysis by phospholipase C and display homologous desensitization. The experiments of neurotransmitter release indicated that both peptides at 10nM induced an increase in the release of the glutamate analogue [3H]-D-aspartate preloaded to cerebellar granule cells in culture. Therefore, cultured cerebellar granule cells can provide an excellent model for investigating he biochemical mechanisms and physiological role of ET receptors in the brain.